Nlrp6 regulates intestinal antiviral innate immunity

Nlrp6 keeps gut infections in check Most viruses infect only certain cells of the body. Enteric viruses, such as norovirus and rotavirus, specifically infect the gut. Wang et al. now show that the response to such viruses is tissue-specific, too. Antiviral immunity to enteric but not systemic viral infections in mice required Nlrp6, a member of the NOD-like receptor family of proteins that play important roles in host defense. Together with the RNA helicase protein Dhx15, Nlrp6 bound viral RNA and elicited downstream antiviral immune responses necessary for viral clearance. These included the production of type I and type III interferons and the expression of interferon-stimulated genes. Science, this issue p. 826 Control of gut but not systemic viral infections in mice requires the protein NLRP6. The nucleotide-binding oligomerization domain–like receptor (Nlrp) 6 maintains gut microbiota homeostasis and regulates antibacterial immunity. We now report a role for Nlrp6 in the control of enteric virus infection. Nlrp6−/− and control mice systemically challenged with encephalomyocarditis virus had similar mortality; however, the gastrointestinal tract of Nlrp6−/− mice exhibited increased viral loads. Nlrp6−/− mice orally infected with encephalomyocarditis virus had increased mortality and viremia compared with controls. Similar results were observed with murine norovirus 1. Nlrp6 bound viral RNA via the RNA helicase Dhx15 and interacted with mitochondrial antiviral signaling protein to induce type I/III interferons (IFNs) and IFN-stimulated genes (ISGs). These data demonstrate that Nlrp6 functions with Dhx15 as a viral RNA sensor to induce ISGs, and this effect is especially important in the intestinal tract.

[1]  Maxim N. Artyomov,et al.  Interferon-λ cures persistent murine norovirus infection in the absence of adaptive immunity , 2015, Science.

[2]  Bin Yuan,et al.  DHX15 Senses Double-Stranded RNA in Myeloid Dendritic Cells , 2014, The Journal of Immunology.

[3]  H. Ichijo,et al.  The DEAH-Box RNA Helicase DHX15 Activates NF-κB and MAPK Signaling Downstream of MAVS During Antiviral Responses , 2014, Science Signaling.

[4]  Zhigang Zhang,et al.  NLRC3, a member of the NLR family of proteins, is a negative regulator of innate immune signaling induced by the DNA sensor STING. , 2014, Immunity.

[5]  E. Elinav,et al.  NLRP6 Inflammasome Orchestrates the Colonic Host-Microbial Interface by Regulating Goblet Cell Mucus Secretion , 2014, Cell.

[6]  E. Fikrig,et al.  UBXN1 interferes with Rig-I-like receptor-mediated antiviral immune response by targeting MAVS. , 2013, Cell reports.

[7]  R. Germain,et al.  The Adaptor MAVS Promotes NLRP3 Mitochondrial Localization and Inflammasome Activation , 2013, Cell.

[8]  Ruth R. Montgomery,et al.  IL-22 Signaling Contributes to West Nile Encephalitis Pathogenesis , 2012, PloS one.

[9]  B. Koller,et al.  The innate immune sensor NLRC3 attenuates Toll-like receptor signaling via modification of the signaling adaptor TRAF6 and transcription factor NF-κB , 2012, Nature Immunology.

[10]  Xian Chen,et al.  The mitochondrial proteins NLRX1 and TUFM form a complex that regulates type I interferon and autophagy. , 2012, Immunity.

[11]  J. Bertin,et al.  NLRP6 Negatively Regulates Innate Immunity and Host Defense Against Bacterial Pathogens , 2012, Nature.

[12]  J. Cui,et al.  Enhanced TLR-induced NF-κB signaling and type I interferon responses in NLRC5 deficient mice , 2012, Cell Research.

[13]  Richard A. Flavell,et al.  Inflammasomes in health and disease , 2012, Nature.

[14]  M. Bertrand,et al.  NOD-like receptors and the innate immune system: coping with danger, damage and death. , 2011, Cytokine & growth factor reviews.

[15]  P. Ranjan,et al.  NLRX1 protein attenuates inflammatory responses to infection by interfering with the RIG-I-MAVS and TRAF6-NF-κB signaling pathways. , 2011, Immunity.

[16]  Richard A. Flavell,et al.  NLRP6 Inflammasome Regulates Colonic Microbial Ecology and Risk for Colitis , 2011, Cell.

[17]  M. Hornef,et al.  IFN-λ determines the intestinal epithelial antiviral host defense , 2011, Proceedings of the National Academy of Sciences.

[18]  A. Aderem,et al.  The NLRP3 Inflammasome Detects Encephalomyocarditis Virus and Vesicular Stomatitis Virus Infection , 2011, Journal of Virology.

[19]  M. Kagnoff,et al.  RIG-I/MDA5/MAVS Are Required To Signal a Protective IFN Response in Rotavirus-Infected Intestinal Epithelium , 2011, The Journal of Immunology.

[20]  H. Sultana,et al.  Caspase-12 controls West Nile virus infection via the viral RNA receptor RIG-I , 2010, Nature Immunology.

[21]  Zhijian J. Chen,et al.  NLRC5 Negatively Regulates the NF-κB and Type I Interferon Signaling Pathways , 2010, Cell.

[22]  Kaoru Tominaga,et al.  Activation of innate immune antiviral response by NOD2 , 2009, Nature Immunology.

[23]  Xiaoping Zhou,et al.  ERIS, an endoplasmic reticulum IFN stimulator, activates innate immune signaling through dimerization , 2009, Proceedings of the National Academy of Sciences.

[24]  R. Webby,et al.  The intracellular sensor NLRP3 mediates key innate and healing responses to influenza A virus via the regulation of caspase-1. , 2009, Immunity.

[25]  J. Ting,et al.  The NLRP3 inflammasome mediates in vivo innate immunity to influenza A virus through recognition of viral RNA. , 2009, Immunity.

[26]  Kristen D Yetming,et al.  Ganglioside-Linked Terminal Sialic Acid Moieties on Murine Macrophages Function as Attachment Receptors for Murine Noroviruses , 2009, Journal of Virology.

[27]  Akiko Iwasaki,et al.  Inflammasome recognition of influenza virus is essential for adaptive immune responses , 2009, The Journal of experimental medicine.

[28]  Ruth R. Montgomery,et al.  Matrix Metalloproteinase 9 Facilitates West Nile Virus Entry into the Brain , 2008, Journal of Virology.

[29]  M. Heise,et al.  NLRX1 is a regulator of mitochondrial antiviral immunity , 2008, Nature.

[30]  S. Akira,et al.  Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3 , 2006, Nature.

[31]  Ralf Bartenschlager,et al.  Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus , 2005, Nature.

[32]  Osamu Takeuchi,et al.  IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction , 2005, Nature Immunology.

[33]  Z. Zhai,et al.  VISA Is an Adapter Protein Required for Virus-Triggered IFN-β Signaling , 2005 .

[34]  Zhijian J. Chen,et al.  Identification and Characterization of MAVS, a Mitochondrial Antiviral Signaling Protein that Activates NF-κB and IRF3 , 2005, Cell.

[35]  Larissa B. Thackray,et al.  Replication of Norovirus in Cell Culture Reveals a Tropism for Dendritic Cells and Macrophages , 2004, PLoS biology.

[36]  C. Wobus,et al.  STAT1-Dependent Innate Immunity to a Norwalk-Like Virus , 2003, Science.